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Definitions

• Product comprising at least one NO synthase inhibitor substance in combination with at least one phospholipase A2 inhibitor substance
• the invention relates to a product comprising at least one NO synthase inhibitor substance in combination with at least one phospholipase A2 inhibitor substance, in separate form or in combination, for simultaneous, separate or time-dispersed therapeutic use in the treatment of pathologies in which nitrogen monoxide and / or phospholipases A2 are involved.
• the invention also relates to a pharmaceutical composition comprising, as active ingredient, at least one NO synthase inhibitor substance and at least one phospholipase A2 inhibitor substance, and optionally a pharmaceutically acceptable carrier.
• a product and a pharmaceutical composition according to the invention are advantageous in the treatment of pathologies where nitrogen monoxide and phospholipases A2 are involved, and in particular:
• - proliferative, inflammatory and edematous diseases such as, for example, atherosclerosis, restenosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis , inflammation of the gastrointestinal system (colitis, Crohn's disease, pancreatitis) or of the pulmonary and airways system (asthma, sinusitis, respiratory distress syndrome), allergic rhinitis;
• cardiovascular and cerebrovascular disorders including, for example, migraine, arterial hypertension, septic shock, cardiac or cerebral infarction of ischemic or hemorrhagic origin, ischemia and thrombosis;
• - disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases where one can in particular cite cerebral infarctions, senile dementias, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob's disease, diseases due to prions, amyotrophic lateral sclerosis but also pain, brain or spinal cord injuries, addiction to opiates, alcohol and addictive substances; - dermatitis, solar radiation (UVA, UVB);
• autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis, myopathies;
• drugs that can inhibit the formation of nitric oxide or inhibit phospholipases A2 can provide beneficial effects.
• active ingredients acting by different mechanisms causes an unexpected therapeutic effect of these active ingredients, namely that they act synergistically. Indeed, these, administered at subactive doses (that is to say at doses which do not by themselves produce a therapeutic effect), produce, when combined, a highly significant therapeutic effect. .
• the invention firstly relates to a product comprising at least one NO synthase inhibitor substance in combination with at least one phospholipase A2 inhibitor substance, in separate form or in combination, for use simultaneous, separate or spread over time in the treatment of pathologies in which nitric oxide and / or phospholipases A2 are involved.
• said product will comprise a substance inhibiting NO synthase in association with a substance inhibiting phospholipases A2.
• inhibitor of NO synthases any specific or non-specific inhibitor of one of its isoforms whether it is constitutive (neuronal or endothelial) or inducible (J. Med. Chem. (1995) 38, 4343-4362) .
• the NO synthase inhibitors used for the present invention will be inhibitors of the neuronal or inducible forms of NO synthases.
• phospholipase A2 inhibitor any specific or non-specific inhibitor of one of the secreted or cellular forms of phospholipase A2 (Medicine / Sciences (1995) 12, 323-332; Trends Pharmac. Sci. (1999) 20, 16162-16170; Brain Res. Bull. (1999) 49, 139-153).
• the inhibitor of NO synthases and the inhibitor of phospholipases A2 can be present in separate form or in combined form by forming a salt.
• the salt is formed from a derivative of the NO synthase inhibitor substance containing at least one basic group and from a phospholipase A2 inhibitor derivative containing at least one acid group.
• salts can be formed, according to methods known to those skilled in the art, from inhibitors of NO synthase such as for example amidines, guanidines, pyridines or piperidines as defined below, and inhibitors of phospholipases A2 such as for example mepacrine, aristolochic acid, acylpyrroldicarboxylic acids or acylindoldicarboxylic acids as defined below.
• inhibitors of NO synthase such as for example amidines, guanidines, pyridines or piperidines as defined below
• inhibitors of phospholipases A2 such as for example mepacrine, aristolochic acid, acylpyrroldicarboxylic acids or acylindoldicarboxylic acids as defined below.
• a subject of the invention is also a product comprising at least one NO synthase inhibitor substance in association with at least one phospholipase A2 inhibitor derivative, in separate form or in combination, for simultaneous, separate or spread over time in therapeutic use.
• pathologies in which nitric oxide and / or phospholipases A2 are involved such as in particular cardiovascular and cerebrovascular disorders, disorders of the central or peripheral nervous system, proliferative and inflammatory diseases, organ transplants, autoimmune and viral diseases, cancer, and more generally all pathologies characterized either by an excessive production of nitric oxide and / or phospholipases A2, or by a dysfunction linked to nitrous oxide and / or phospholipases A2.
• the amino acid and non-amino acid type compounds can be defined.
• the NO synthase inhibitors of the amino acid type can be compounds as described in applications WO 95/00505, WO 94/12163, WO 96/06076 and application EP 230037, incorporated by reference in the present application, or alternatively derivatives of L-arginine, ornithine or lysine as described in PCT applications WO 93/24126, WO 95/01972, WO 95/24382, WO 95/09619 and WO 95/22968, incorporated by reference in this application.
• Non-amino acid type NO synthase inhibitors can be compounds from the family of guanidines, isothioureas, nitro- or cyano-aryls, amino-pyridines or amino-pyrimidines, amidines, indazoles or imidazoles .
• the NO synthase inhibitor guanidine derivatives can be the compounds as defined in PCT applications WO 95/28377, WO 91/04023, WO 94/21621, WO 96/18607 and WO 96/18608 incorporated by reference in the present application .
• the NO synthase inhibitor isothioureas can be the compounds as defined in PCT applications WO 95/09619, WO 96/09286, WO 94/12165, WO 96/14842, WO 96/18607, WO 96/18608, WO 96 / 09286 and EP 717040 and EP 718294 incorporated by reference in this application.
• nitro- or cyano-aryl inhibitors of NO synthases may be the compounds as defined in PCT application WO 94/12163, incorporated by reference in the present application.
• Amino-pyridines or amino-pyrimidines inhibitors of NO synthases can be the compounds as defined in PCT applications WO 94/14780, WO 96/18616 and WO 96/18617, incorporated by reference in the present application.
• the NO synthase inhibiting amidines can be the compounds as defined in PCT applications WO 95/11014, WO 96/01817, WO 95/05363, WO 95/11231, WO 96/14844 and WO 96/19440 incorporated by reference in the present application, or compounds such as N-phenyl-2-thiophenecarboximidamide.
• inhibitors of NO synthases can also be both inhibitors of NO synthases (NOS) and scavengers of reactive forms of oxygen (ROS for Reactive Oxygen Species).
• NOS NO synthases
• ROS reactive forms of oxygen
• the NO synthase inhibitor indazoles can be compounds of general formula I A
• R 1 represents one or more substituents chosen from the hydrogen atom and the nitro, halo, alk 1 or alkoxy radicals;
• NO synthase inhibitor imidazoles can be the compounds of general formula II A
• Ri and R independently represent a hydrogen atom or the halo, hydroxy, amino, alkyl or alkoxy radical, or R] and R are linked together and form a phenyl radical condensed with the imidazole ring, said radical phenyl being optionally substituted by one or more substituents chosen from hydroxy, trifluoromethyl, halo, carboxy, alkyl, alkoxy or alkenyl radicals;
• R 3 represents a hydrogen atom or an alkyl, amino, alkylamino or phenyl radical, said phenyl radical being optionally substituted by one or more substituents chosen from hydroxy, trifluoromethyl, halo, carboxy, alkyl, alkoxy or alkenyl radicals; and
• R 4 represents a hydrogen atom or an alkyl, amino or alkylamino radical;
• the NO synthase and ROS inhibitor compounds can in particular be the compounds of general formula III A
• A is a radical
• R 1 and R 2 independently represent a hydrogen atom, a halogen, the OH group, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to 6 atoms of carbon
• R3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR 4 radical
• R 4 representing an alkyl radical having from 1 to 6 carbon atoms, or a radical
• R 3 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a -COR 4 radical, R 4 representing an alkyl radical having from 1 to 6 carbon atoms;
• B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, phenyl, pyridinyl or a 5-membered heterocycle containing from 1 to 4 heteroatoms chosen from O, S, N and more particularly: thiophene, furan, pyrrole or thiazole , the carbons of which are optionally substituted by one or more groups chosen from an alkyl radical having from 1 to 6 linear or branched carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms or a halogen;
• Y represents -Y'-, -CO-NH-Y ⁇ -Y'-NH-CO-, -CO-Y'-, -Y'-CO, -N (R 3 ) -Y'-, -Y ' -N (R 3 ) -, Y'-CH 2 -N (R 3 ) -CO-, -O-Y'-, -Y'-O-, -S-Y'-, -Y'-S- , -Y'-O-Y'-, -Y'-N (R 3 ) -Y'- or a bond, Y 'representing - (CH 2 ) n - with n integer from 0 to 6;
• Het represents a heterocycle comprising from 1 to 5 heteroatoms chosen from O, N, S which may be substituted by one or more substituents X'-OR3, X'-NR 3 , X'-SR 3 and such as for example: oxetane, pyrrole , pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulfolane, piperazine, homopiperazine,
• the compounds of the present invention may have asymmetric carbon atoms. Therefore, the compounds of the present invention have two possible enantiomeric forms, i.e., the "R” and “S” configurations.
• the compounds of the present invention include the two enantiomeric forms and all combinations of these forms, including the racemic mixtures "RS". For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.
• alkyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms.
• alkenyl when it is not given more precision, is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one unsaturation (double bond).
• haloalkyl is meant an alkyl radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom.
• alkoxy alkenyl or alkylamino radicals is meant respectively the alkoxy, alkenyl or alkylamino radicals, the alkyl radical of which has the meaning indicated above.
• linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
• halogen is meant the fluorine, chlorine, bromine or iodine atoms.
• pharmaceutically acceptable salt means in particular the addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate.
• inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate.
• bases such as sodium or potassium hydroxide.
• the compounds of the acylpyrroldicarboxylic acids, acylindoldicarboxylic acids and pyrrolidine derivatives type can be defined.
• the phospholipase A2 inhibitors of the acylpyrroldicarboxylic acid, acylindoldicarboxylic acid and pyrrolidine derivative type can be compounds as described in applications EP 97934481, WO 98/05637, EP 969225076 and WO 98/33797.
• the phospholipase A2 inhibitors can also be the compounds as defined in applications WO 99/43672, WO 99/43654, WO 99/43651, WO 99/15493 and WO 98/37069.
• the phospholipase A2 inhibitors can in particular also be derivatives of arylsulfonamides as described in application WO 98/25893, derivatives of 1H-indole-3-glyoxylamide such as those described in application WO 99/57100, derivatives of indoles such as those described in application WO 00/07591 or derivatives of 2-phenylpyrimidines such as those described in application WO 00/27824. All of the above patent applications are incorporated by reference into the present application.
• the A2 phospholipase inhibitors will preferably be:
• RI represents a group -Yl-Ar-Y2-Y3 in which Yl and Y2 independently represent a (C, -C 12 ) -alkyl, (C 2 -C 12 ) -alkenyl, (C, -C I2 ) -alkoxy radical or (C, -C, 2 ) -alkenyloxy, the radicals Yl and Y2 possibly being interrupted by one or more oxygen atoms, Ar is an aryl group optionally substituted from 1 to 3 times by substituents chosen independently from the groups R6, R7 and R8, and Y3 represents a radical -COOR17, -CONR17R17, -CONHCOR19, -CONHS (O) 2 R19, -CONHNHS (O) 2 R19 or Tz; R2 represents -COOR17, -Y4-COOR17, -CONR17R17, -Y4-CONR17R17, -CONHCOR19, -Y
• Tz is a 1H- or 2H-tetrazol-5-yl radical; the radicals R6, R7, R8, RIO, R11, R12, R13, R14, R15 and R16 are independently selected from the group consisting of (C, -C 20 ) -alkyl, (C 2 -C 20 ) -alkenyl or (C 2 -C 20 ) -alkynyl optionally interrupted by one or more oxygen atoms, a halogen atom, the groups -CF 3 , -CN, -NO 2 or -COCH, OH and a perhalo radical (C, -C 6 ) -alkenyl, -OR17, -SRI 7, -COOR17, -COR18, -NHCOR17, -NR17R17, -NHS (O) 2 R17, -SOR17, -S (O) 2 R17, -CONR17R17, -S (O ) 2
• RI 7 represents, independently each time it occurs, a radical - (CH 2 ) ( R20 or one of the radicals (C
• RI 8 represents, independently each time it occurs, a radical RI 7, -CF 3 , - (CH 2 ) u COOH or- ( CH 2 ) u COOR21;
• RI 9 represents, independently each time it occurs, a radical RI 7 or -CF 3 ;
• R20 represents, independently whenever it occurs, an aryl radical substituted by one or two R22 groups
• R21 represents, independently each time it occurs, a (C, -C 6 ) -alkyl, benzyl or phenyl radical
• R22 represents, independently each time it occurs, a hydrogen atom, a halogen atom, a (C, -C 12 ) -alkyl, (C, -C 12 ) -alkoxy, (C, -C 12 ) -alkylthio, (C, -C I2 ) -alkylsulfonyl, (C, -C 12 ) -alkylcarbonyl, -CF 3 , -CN or -NO 2 ;
• R23 represents, independently each time it occurs, a hydrogen atom or a -COR21 radical; r is an integer from 1 to 20; s and t independently represent integers from 0 to 12; and u represents an integer from 0 to 4;
• RI is chosen from the group consisting of radicals
• RIO is independently chosen from a halogen atom and a (C, -C I0 ) -alkyl, (C r C I0 ) -alkoxy, (C, -C I0 ) -alkylthio and (C, -C 10 ) - radical haloalkyl and t is an integer from 0 to 5;
• R2 is chosen from a halogen atom and a cyclopropyl, methyl, ethyl or propyl radical;
• R4 and R5 are independently chosen from a hydrogen atom, a non-interfering substituent or the group (acid) -L a - (acid group), it being understood that -L a - for R4 is chosen from -O-CH 2 -, -S-CH 2 -, -NH-CH 2 -, -CH 2 -CH 2 -, -O-CH (CH 3 ) - and -O-CH (CH 2 -CH 2 -Ph) -, Ph being a phenyl radical and that -L a - for R5 is chosen from the radicals
• R84 and R85 are independently selected from a hydrogen atom, a halogen atom and a (C, -C 10 ) -alkyl, aryl, (C, -C 10 ) -alkaryl, (C, -C 10 ) radical -aralkyl, carboxy or carbalkoxy, it being also understood that at least one of R4 and R5 must be the group -L a - (acid group) and that the (acid group) of R4 and R5 is chosen from -CO 2 H , -SO 3 H and -P (O) (OH) 2 ;
• R6 and R7 are independently selected from a hydrogen atom and a non-interfering substituent; the non-interfering substituents being independently selected from the group consisting of (C, -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 ) -alkynyl radicals,
• RI is chosen from groups (a), (b) and (c);
• (a) represents a (C 7 -C 20 ) -alkyl, (C 7 -C 20 ) -haloalkyl, (C 7 -C 20 ) -alkenyl or (C 7 -C 20 ) -alkynyl radical, a carbon ring of 5 to 14 membered saturated or unsaturated optionally substituted with one or more substituents chosen from non-interfering substituents, or alternatively (a) represents a 5 to 14 membered heterocycle containing from 1 to 3 heteroatoms, said heterocycle being saturated or unsaturated and optionally substituted with one or more substituents chosen from non-interfering substituents;
• (b) is one of the radicals (a) substituted with one or more substituents chosen from non-interfering substituents;
• (c) represents the group - (L,) - R11 in which - (L,) - is a group chosen from the groups represented by the formulas
• Q represents a bond or one of the groups -CH 2 -, -O-, -S-, -NH- and -CO- and each of the RIO groups independently represents a hydrogen atom or a radical (C , -C 8 ) -alkyl, (C, -C 8 ) -haloalkyl or (C, -C 8 ) -alkoxy, and RI 1 is a group chosen from groups (a) and (b);
• R2 is a hydrogen atom, a halogen atom, or a (C, -C 4 ) -alkyl, (C 2 -C 4 ) -alkenyl, -O- (C, -C 3 ) -alkyl, -S radical - (C, -C 3 ) -alkyl, - (C, -C 4 ) -cycloalkyl, -CF 3 , -NO 2 , -CN or -SO 3 ;
• R3 represents - (L 3 ) -Z in which - (L 3 ) - is a divalent linking group chosen from a bond and the groups -CH 2 -, -O-, -S-, -NH- and -CO- ; and Z is chosen from the acetamide, thioacetamide, glyoxylamide, thioglioxylamide, hydrazide or thiohydrazide groups represented by the general formulas in which R31 and R32 are independently chosen from a hydrogen atom and a (C, -C 8 ) -alkyl, (C, -C 8 ) -haloalkyl or (C 3 -C 4 ) -cycloalkyl radical and X represents, independently each time it intervenes, an oxygen or sulfur atom; R4 and R5 are independently chosen from a hydrogen atom, a non-interfering substituent or the group - (LJ- (acylsulfonamide group) in which
• each of the R40 groups is independently chosen from a hydrogen atom, a halogen atom and (C, -C 8 ) -alkyl, aryl, (C, -C 8 ) -alkaryl, (C, -C 8 ) -alkoxy and aralkyl radicals, - (LJ- for R5 is chosen from the groups represented by formulas
• R54, R55, R56 and R57 are independently chosen from the group consisting of a hydrogen atom, a halogen atom and (-C -alkyl, (C, -C 8 ) -alkoxy, (- C ⁇ -haloalkyl and aryl, the group (acylsulfonamide) being a group of formula -CO-NH-SO 2 -R81 in which R81 is chosen from the group consisting of radicals -CF 3 , (C, -C 8 ) -alkyl , (C, -C 8 ) -alkoxy, (C, -C 8 ) -alkylthio, (C, -C 8 ) -alkylamino, (C, -C 8 ) -haloalkyl, (C, -C 14 ) -aralkyl, (C, -C 14 ) -alkylaryl, aryl, thioaryl, (C 3 -
• R6 and R7 independently represent a hydrogen atom, a non-interfering substituent, a 5 to 14-membered saturated or unsaturated carbon ring optionally substituted by one or more substituents chosen from non-interfering substituents or a heterocycle from 5 to 14 links containing from 1 to 3 heteroatoms, said heterocycle being saturated or unsaturated and optionally substituted by one or more substituents chosen from substituents which do not interfere; the non-interfering substituents being independently selected from the group consisting of (C, -C 8 ) -alkyl, (C 2 -C 8 ) -alkenyl, (C 2 -C 8 ) -alkynyl, (C 7 -C) radicals 12 ) -aralkyl, (C 7 -C 12 ) -alkaryl, (C 3 -C 8 ) -cycloalkyl, (C 3 -C 8 ) -cycloalkenyl, phenyl, tol
• R1 is chosen from the group consisting of a halogen atom and (C, -C 6 ) -alkyl or (C, -C 6 ) -alkoxy radicals;
• R2 is chosen from the group consisting of one of the phenyl or benzyl radicals optionally substituted on the aromatic ring by a halogen atom or a (C r C 6 ) -alkyl, (C, -C 6 ) -alkoxy, amino, alkylamino radical , dialkylamino, carboxyl, carbamoyl, (C, -C 8 ) -acyl, sulfonyl, thiol or alkylthio, and of a (C 3 -C 7 ) -cycloalkyl radical, said (C 3 -C 7 ) -cycloalkyl radical being optionally condensed with a benzene ring or a heterocycle and being optionally substituted by a halogen atom or a (C, -C 6 ) -alkyl radical; R3 is chosen from the group consisting of a halogen atom and a (C, -C 6 )
• the phospholipase A2 inhibitors may be chosen from the group consisting of mepacrine, aristolochic acid and their analogs, as well as the pharmaceutically acceptable salts of the latter.
• the subject of the invention is more particularly a product as defined above, characterized in that:
• the inhibitor (s) of NO synthases are chosen from the group consisting of L-nitro-arginine (LNA), the methyl ester of L-nitro-arginine (LNAME), LN-monomethylarginine (LNMMA), aminoguanidine, agmatine, 2-amino- l- (methylamino) benzimidazole, 5-nitro-indazole, 6-nitro-indazole, 7-nitro-indazole, l, 2- (trifluoromethylphenyl) imidazole (TRIM ), 2-amino-4-methyl- 6- (2-aminoethyl) pyridine, 2-iminopiperidine, 2-iminohomopiperidine, 2-imino-5,6-dihydro-1,3-thiazine, 2- imino-5,6-dihydro-1,3-oxazine, N-phenyl-2-thiophenecarboximidamide, 2-iminotetrahydropyrimidine, S-e
• the invention relates to a product as defined above, characterized in that:
• the inhibitor (s) of NO synthases are chosen from the group consisting of aminoguanidine, 7-nitro-indazole and 4- [3,5-bis (1,1-dimethylethyl) -4- hydroxyphenyl] -N- ⁇ 4 - [(imino (2-thienyl) methyl) amino] phenyl ⁇ -N-methyl-2-thiazole-methanamine, as well as the pharmaceutically acceptable salts of the above-mentioned compounds; and
• the phospholipase A2 inhibitor (s) are chosen from the group consisting of mepacrine, aristolochic acid and their analogs, as well as the pharmaceutically acceptable salts of the latter.
• a product according to the invention can be used in the treatment of pathologies in which nitric oxide and / or phospholipases A2 are involved.
• pathologies include in particular cardiovascular and cerebrovascular disorders, disorders of the central or peripheral nervous system, proliferative and inflammatory diseases, diarrhea, vomiting, radioactive radiation, solar radiation, organ transplants, autoimmune diseases and viral, cancer, and more generally all pathologies characterized either by an excessive production of nitric oxide and or phospholipases A2, or by a dysfunction related to nitric oxide and / or phospholipases A2.
• a product according to the invention may be used in the treatment of pathologies chosen from proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis and inflammation of the gastrointestinal system or the pulmonary and airways.
• proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis and inflammation of the gastrointestinal system or the pulmonary and airways.
• a product according to the invention can be used in the treatment of autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis or myopathies.
• the subject of the invention is also a pharmaceutical composition comprising, as active principle, at least one NO synthase inhibitor substance and at least one phospholipase A2 inhibitor substance, and optionally a pharmaceutically acceptable carrier.
• said pharmaceutical composition will comprise, as active principle, a substance inhibiting NO synthases and a substance inhibiting phospholipases A2.
• compositions according to the invention will comprise a product as described above, the same preferences remaining applicable.
• the inhibitor of NO synthases and the inhibitor of phospholipases A2 can be present in doses which can be identical or different.
• the dosages are chosen according to the compounds, combined with suitable diluents or excipients.
• the NO synthases inhibitor and the phospholipase A2 inhibitor can be administered simultaneously or sequentially, by the same administration route or by different routes, depending on whether they are presented in a separate or combined form.
• the routes of administration are oral, parenteral or topical.
• a pharmaceutical composition according to the invention may be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories.
• Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
• compositions containing a product according to the invention may also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
• suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
• NO synthase inhibitor compounds and the phospholipase A2 inhibitor compounds are commercially available or can be prepared by methods known to those skilled in the art (or by analogy thereto).
• the compounds of general formula IIIA are described in PCT applications WO 98/42696 and
• WO 98/58934 and the compounds of general formulas I B and I ' B , II B , III B and IV B are described respectively in PCT patent applications WO 98/05637, WO 99/57100, WO 00/07591 and WO 00/27824.
• the activity of the compounds of the invention was evaluated in vivo on a model of carrageenan edema on the rat's paw.
• mice Male Sprague Dawley rats (Charles River) weighing 170 to 180 g on the day of the experiment are kept in a stall for 5 to 8 days under animal house conditions and are fasted on racks 18 hours before and during the experiment.
• the groups are made up of 8 animals.
• the products are administered intraperitoneally (ip, 2 ml / kg), 30 minutes before the 1% carrageenan injected sub plantarly into the right hind paw of the rats.
• the volume of the leg corresponding to the edema is measured using a water plethysmometer (Ugo Basile, APELEX) before the injection of carrageenan (to) and 3 hours after the injection.
• the volume of the paw makes it possible to determine the% of inflammation ((volume of the paw at time t after carrageenan - volume of this same paw at time to before injection of the products / volume of the paw at time to) x 100). Any product capable of significantly reducing the intensity of edema (% of inflammation) will be considered active. This efficiency will be statistically determined by a Student test.
• A denotes the inhibitor of NO synthases and B the inhibitor of phospholipases A2.
• Compound AB combination of the active ingredients A and B.
• Compound A 7-nitroindazole, inhibitor of the neuronal form of NO synthases.
• Compound B mepacrine, phospholipase A2 inhibitor.
• Example 1 Composed of Example 1: 4 groups of animals are made up:
• Group 1 treated with the vehicle + carrageenan.
• Group 2 treated with A (25 mg / kg) + carrageenan.
• Group 3 treated with B (30 mg / kg) + carrageenan.
• Group 4 treated with AB + carrageenan.
• Compound AB combination of active principles A and B in separate form, with compound A: aminoguanidine, inhibitor of the inducible form of NO synthases; and as compound B: mepacrine, inhibitor of phospholipases A2.
• Example 2 Composed of Example 2: 4 groups of animals are made up:
• Group 1 treated with the vehicle + carrageenan.
• Group 2 treated with A (400 mg / kg) + carrageenan.
• Group 3 treated with B (30 mg / kg) + carrageenan.
• Group 4 treated with AB + carrageenan.
• Example 3 Composed of Example 3: 4 groups of animals are made up:
• Group 1 treated with the vehicle + carrageenan.
• Group 2 treated with A (400 mg / kg) + carrageenan.
• Group 3 treated with B (30 mg / kg) + carrageenan.
• Group 4 treated with AB + carrageenan. No. of% inflammation group
• Compound AB combination of active principles A and B in separate form, with as compound A: 4- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] - N- ⁇ 4 - [( imino (2-thienyl) methyl) amino] phenyl ⁇ -N-methyl-2-thiazolemethanamine, a mixed inhibitor of the neuronal form of NO synthases and lipid peroxidation; and as compound B: mepacrine, inhibitor of phospholipases A2.
• Example 4 Composed of Example 4: 4 groups of animals are made up:
• Group 1 treated with the vehicle + carrageenan.
• Group 2 treated with A (30 mg / kg) + carrageenan.
• Group 3 treated with B (30 mg / kg) + carrageenan.
• Group 4 treated with AB + carrageenan. No. of% inflammation group

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